Identification of a Transcription Factor That Regulates Host Cell Exit and Virulence of Mycobacterium tuberculosis

• Published in: PLoS pathogens 2016-05, Vol.12 (5), p.e1005652-e1005652
• Main Authors: Srinivasan, Lalitha, Gurses, Serdar A, Hurley, Benjamin E, Miller, Jessica L, Karakousis, Petros C, Briken, Volker
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Autophagy; Bacteria; Bacterial Proteins - metabolism; Biology and Life Sciences; Cells (Biology); Disease Models, Animal; Experiments; Flow cytometry; Gangrene; Genetic aspects; Guinea Pigs; Health aspects; Immunoblotting; Infections; Kinases; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy; Microscopy, Electron, Transmission; Mycobacterium tuberculosis; Mycobacterium tuberculosis - pathogenicity; Pathogens; Polymerase Chain Reaction; Research and Analysis Methods; Signal transduction; Transcription factors; Transcription Factors - metabolism; Tuberculosis; Tuberculosis - metabolism; Virulence (Microbiology); Virulence - physiology; Virulence Factors - metabolism
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005652

The interaction of Mycobacterium tuberculosis (Mtb) with host cell death signaling pathways is characterized by an initial anti-apoptotic phase followed by a pro-necrotic phase to allow for host cell exit of the bacteria. The bacterial modulators regulating necrosis induction are poorly understood. Here we describe the identification of a transcriptional repressor, Rv3167c responsible for regulating the escape of Mtb from the phagosome. Increased cytosolic localization of MtbΔRv3167c was accompanied by elevated levels of mitochondrial reactive oxygen species and reduced activation of the protein kinase Akt, and these events were critical for the induction of host cell necrosis and macroautophagy. The increase in necrosis led to an increase in bacterial virulence as reflected in higher bacterial burden and reduced survival of mice infected with MtbΔRv3167c. The regulon of Rv3167c thus contains the bacterial mediators involved in escape from the phagosome and host cell necrosis induction, both of which are crucial steps in the intracellular lifecycle and virulence of Mtb.